This is a renewal application for a 5-year continuation of the VITamin D and OmegA-3 TriaL (VITAL), which is evaluating the role of vitamin D and marine omega-3 fatty acid supplements in the primary prevention of cancer and cardiovascular disease (CVD). Evidence for a role of these agents in preventing cancer, CVD, and other diseases remains inconclusive regarding causality and insufficient to inform nutritional recommendations for primary prevention. Appropriately designed randomized trials in general populations are lacking. To fill this knowledge gap, we have been conducting VITAL, a highly innovative, cost-efficient, large-scale, randomized, double-blind, placebo-controlled clinical tria among 26,000 U.S. men and women without cancer or CVD at baseline, who have been selected only on age (men aged e50 and women aged e55), with an oversampling of blacks (ne5000). In a 2x2 factorial design, participants have been randomized to vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (Omacor(R) fish oil, 1 g/d, containing eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) supplements (or placebos) independently. Contingent on continued funding, the median treatment period will be 5 years. During the first cycle, we have successfully met or surpassed our recruitment goals, enrolled a racially/ethnically diverse cohort, collected baseline blood/DNA samples on >16,000 participants (with plans for follow-up bloods in 6000), and conducted extensive validation studies of the laboratory assays for vitamin D and omega-3 fatty acid measurements in the trial. Annual follow-up questionnaires assess treatment compliance (confirmed by blood samples in a subset of participants), side effects, endpoint occurrence, and cancer and vascular risk factors. Self-reported endpoints are confirmed by medical record review by physicians blinded to treatment assignment, and deaths are ascertained through the National Death Index-Plus and other sources. Our archived blood samples allow assessment of effect modification by baseline 25-hydroxyvitamin D and omega-3 fatty acid levels, changes in biomarkers over time, and testing of genetic/biochemical hypotheses. With our scientific colleagues, we have obtained funding for 18 ancillary studies to evaluate the role of these supplements in preventing other chronic diseases (including diabetes, cognitive decline, depression, and autoimmune disorders), and established an in-clinic component for in-depth phenotyping of a subcohort (n=1000). The trial is expected to provide either definitive positive or informative null results for our primary hypotheses and will serve as a national resource for research on the health effects of vitamin D and omega-3 fatty acids, with opportunities for extensive collaborations. This is a high-impact trial due to the potential for major clinical and public health implications of the findings.